Page 211 - Medicinal Chemistry Self Assessment

2.21 Phenobarbital and Other Barbiturates

Shown below are the structures of buta
O
O
O
O
O
N
H
NH
H
N
NH
NH
H
N
O
O
O
Butabarbital
Secobarbital

1. Conduct a structural previously listed.
Answer:
These three drug to their site of action.

Only site of
variation O Phenobarbital
5
Imide Imide
1 3
200 Medicinal Chemistry Self Assessment
Barbituric Acid

2. Butabarbital and secobarbital are marketed as their sodium salts and phenobarbital is marketed in its
free acid form (i.e., non-salt form). Draw the sodium salt of either butabarbital or secobarbital and

provide an explanation as to why these two drug molecules need to be administered as their sodium
salts. 2. Butabarbital and secobarbital these two administered as their sodium salts.
Answer Answer:
Sodium Butabarbital Sodium Secobarbital Phenobarbital
(Used as Free Acid)

In general the primary reason that drug molecules are administered in their inorganic salt form is to
3. Using the information in acting agent (onset of action = 30–60 minutes; duration = 10–16 hours).
enhance solvation, dissolution, and water solubility. Butabarbital and secobarbital need to be admin-
istered as their sodium salts, whereas phenobarbital does not. This suggests that butabarbital and

secobarbital have greater lipid solubilities than phenobarbital and therefore need to be administered

in a more water soluble form. The authors do not expect the readers to know the structure-activity

relationship (SAR) of barbiturates, so the following information is offered to show how the logical
application of key concepts often explains known facts. Structural activity studies of barbiturates

have demonstrated that alkyl chains at the 5 position of barbituric acid produce more lipid solubility
than the aromatic ring in the structure of phenobarbital. Phenobarbital has a log P value=1.46, while
butabarbital and secobarbital have log P values=1.60 and 2.36, respectively.
3. Using the information in questions 1 and 2, and your answers to those questions, provide an explanation
as to why secobarbital is a short-acting agent (onset of action = 10–15 minutes; duration = 3–4 hours),
butabarbital is an intermediate-acting agent (onset of action = 45–60 minutes; duration = 6–8 hours), and
phenobarbital is a long-acting agent (onset of action = 30–60 minutes; duration = 10–16 hours).
Answer
As discussed in the previous two questions, these three drug molecules are structurally similar and
vary only in the hydrocarbon chains at position 5 of the barbituric acid ring. These minor structural
variations result in differences in their respective lipid solubilities. Drug molecules that have higher
lipid solubility (log P) traverse more quickly through lipid membranes, but are more likely to undergo
metabolic transformation than drug molecules that have lower lipid solubility. Secobarbital is the
most lipid soluble of the three drug molecules. As such, it is rapidly absorbed, can rapidly cross the
blood–brain barrier, and has the quickest onset of action. Due to its higher lipid solubility, it is metab-
olized quicker than either butabarbital or phenobarbital. This rapid metabolism is responsible for the
relatively short duration of action. Butabarbital and phenobarbital are less lipid soluble than secobar-
bital and have similar onsets of action; however, phenobarbital has a lower lipid solubility, is metabo-
lized at a slower rate, and thus has a longer duration of action than butabarbital.